Substituted glutarimides and their use as inhibitors of IL-12 production

ABSTRACT

Substituted glutarimides of formula I  
                 
 
     and their method of making. Also disclosed are pharmaceutical compositions comprising the glutarimidie, particularly as immunomodulators and as inhibitors of angiopathies, or haematological or oncological diseases, as well as a method for treating various diseases using the glutarimides.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation-in-part ofinternational patent application no. PCT/EP01/00155, filed Jan. 9, 2001,designating the United States of America, the entire disclosure of whichis incorporated herein by reference. Priority is claimed based onFederal Republic of Germany patent application no. 100 02 509.9, filedJan. 21, 2000.

FIELD OF THE INVENTION

[0002] The invention concerns substituted glutarimides having thegeneral formula I

[0003] their production and their use in medicaments.

BACKGROUND OF THE INVENTION

[0004] Autoimmune diseases arise as a result of a reactivity of theimmune system against structures or components occurring naturally inthe body. As part of this process, the normally existing tolerancetowards the body's own tissue lapses. In addition to antibodies,T-lymphocytes and monocytes/macrophages in particular play a significantrole in the pathogenesis of the various autoimmune diseases. Activatedmonocytes and/or macrophages secrete a number of differentproinflammatory mediators that are directly or indirectly responsiblefor destroying the tissue affected by the autoimmune disease. Theactivation of monocytes/macrophages occurs either in the interactionwith T-lymphocytes or via bacterial products such as lipopolysaccharide(LPS).

[0005] IL-12 is a heterodimeric molecule consisting of a covalentlybonded p35 and p40 chain. The molecule is formed by antigen-presentingcells (monocytes/macrophages, dendritic cells, B-lymphocytes). Theformation of 1L-12 by monocytes/macrophages is triggered either byvarious microbial products such as LPS, lipopeptides, bacterial DNA orin the interaction with activated T-lymphocytes (Trinchieri, 1995, Ann.Rev. Immunol. 13: 251). IL-12 has a central immunoregulatorysignificance and is responsible for the development of proinflammatoryTH1 reactivities. The presence of a TH1 immune reaction againstself-antigens leads to the occurrence of serious diseases.

[0006] The significance of inflammatory cytokines such as IL-12 for thedevelopment and course of inflammations and autoimmune diseases has beenclearly documented by numerous animal experimental and preliminaryclinical trials. The pathophysiological importance of IL-12 has beendemonstrated in various animal models for diseases such as rheumatoidarthritis, multiple sclerosis, diabetes mellitus and inflammatorydiseases of the intestines, skin and mucous membranes (Trembleau et al.,1995, Immunol. Today 16: 383; Muller et al., 1995, J. Immunol. 155:4661; Neurath et al., 1995, J. Exp. Med. 182: 1281; Segal et al., 1998,J. Exp. Med. 187: 537; Powrie et al., 1995, Immunity 3: 171; Rudolphi etal., 1996, Eur. J. Immunol. 26: 1156; Bregenholt et al., 1998, Eur. J.Immunol. 28: 379). Application of IL-12 could trigger the relevantdisease and neutralisation of endogenous IL-12 led to the course of thedisease being moderated, or even the cure of the animals. The use ofantibodies against IL-12 in humans is imminent.

[0007] It can be said in summary that an excess of IL-12 conditions thepathophysiology of a number of inflammatory diseases. Attempts tonormalize the IL-12 level therefore have great therapeutic potential.

[0008] IL-12 is also involved in regulating the survival of cells.Uncontrolled cell growth is regulated by apoptosis (programmed celldeath) amongst other things. Using T-lymphocytes it has been shown thatIL-12 has an anti-apoptotic action and promotes the survival of T-cells(Clerici et al., 1994, Proc. Natl. Acad. Sci. USA 91: 11811; Estaquieret al., 1995, J. Exp. Med. 182: 1759). A local overproduction of IL-12can therefore contribute to the survival of tumour cells.

[0009] Inhibitors of IL-12 formation therefore possess great therapeuticpotential.

[0010] One potential inhibitor of IL-12 formation is the known activeagent thalidomide (Journal of Immunology 159 (10), 5157-5161 (1997)).

[0011] U.S. Pat. No. 5,114,937 describes renin-inhibiting peptidederivatives, the carboxamide groups in which are replaced by theirisosteres. The compounds are suitable for the treatment ofrenin-associated hypertension, congestive heart failure,hyperaldosteronism, glaucoma and diseases caused by the retrovirusesHTLV-I, —II and —III.

[0012] DE 198 43 793 describes substituted benzamides withimmunomodulatory properties in which the ring-containing structuralparts of the molecule are linked together by an amide bond. Thedisadvantage of the amide bond is its susceptibility to hydrolysis withan accompanying loss of action for the compound.

[0013] The object of the invention was therefore to develop newimmunomodulators that are suitable for the treatment and/or prophylaxisof diseases caused by formation of the proinflammatory cytokine IL-12and that at the same time display an improved hydrolytic stability.

DETAILED DESCRIPTION OF THE INVENTION

[0014] It has now been discovered that substituted glutarimides satisfythe above requirements.

[0015] The invention accordingly provides substituted glutarimideshaving the formula I

[0016] in which X denotes a group having the formula CH₂—NH or S—CH₂,

[0017] R¹ stands for a carboxyl group; an ester group having the formulaCOOR⁵ in which R⁵ denotes an alkyl group (straight-chain or branched)with 1 to 6 carbon atoms or a benzyl radical; or an amide group havingthe formula CONR⁶R⁷, in which R⁶ and R⁷ are the same or different andrepresent hydrogen, an alkyl group (straight-chain or branched) with 1to 6 Carbon atems (optionally substituted with the radical COOR⁵ and/ora phenyl group), a phenyl radical or taken together with the N atomrepresent a hydrazide group, a pyrrolidine, piperidine or morpholinering or stand for an amino group substituted with the radical CH(═O) orCOR⁵, in which R⁵ is as defined above, and

[0018] R² stands for hydrogen, an amino or nitro group,

[0019] and enantiomers, mixtures of enantiomers, racemates,diastereomers or mixtures of diastereomers thereof in the form of theirbases or salts with physiologically compatible acids.

[0020] The following substituted glutarimides are particularlypreferred:

[0021] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,

[0022] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,

[0023]2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,

[0024] (3S)-[2-morpholine-4-carbonyl)benzylamino] piperidine-2,6-dione,

[0025] {2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoylamino}methyl acetate,

[0026] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,

[0027] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl benzamide,

[0028] (3S)-[2-pyrrolidine-1-carbonyl)benzylamino] piperidine-2,6-dione,

[0029] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acidhydrazide,

[0030] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,

[0031] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,

[0032] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,

[0033] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,

[0034] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methyl benzoate,

[0035] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzyl benzoate,

[0036] 2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate,

[0037] N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} acetamide,

[0038] N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} formamide,

[0039] 3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitromethylbenzoate, and

[0040] 2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methylbenzoate.

[0041] The present invention also provides methods for the production ofcompounds according to the invention having the general formula I.

[0042] Compounds having the general formula I can be obtained bycyclizing glutaric acid derivatives having the general formula II,

[0043] in which X, R¹ and R² have the same meaning as defined above forformula I, A stands for OH, B for NH₂ or NHOH, or vice versa, in thepresence of activating reagents such as carbonyl diimidazole. If X inthe compound having the formula I denotes a CH₂—NH group, cyclization ispreferably performed with compounds having the formula II, in which theNH function is present in protected form, for example with a benzyloxycarbonyl group, which is then removed at a temperature of between 20and 40° C., e.g. with a solution of hydrogen bromide in acetic acid.

[0044] Heating a compound of formula II in which A and B both stand forOH in acetic anhydride, first produces a cyclization to the cyclicanhydride, from which the compound having formula I is obtained byheating with urea or another nitrogen source.

[0045] Compounds having the general formula I can also be produced fromlactams having the general formula III,

[0046] in which R¹, R² and X have the same meanings as defined above forformula I, by oxidizing compound III to an imide, preferably withm-chloroperbenzoic acid or ruthenium(IV) oxide/sodium periodate.

[0047] Compounds having the formula I, in which X stands for the CH₂—NHgroup, can also be obtained by alkylating α-aminoglutarimides having thegeneral formula IV,

[0048] with compounds having the general formula V,

[0049] in which R¹ and R² have the same meanings as above and Y standsfor a chlorine, bromine or iodine atom or a toluene-4-sulfonate radical.

[0050] Compounds in which X stands for the CH₂—NH group can also beobtained by reductive amination from compounds having the generalformulae VI and IV, in which R¹ and R² have the same meanings as above.

[0051] Sodium borohydride, sodium triacetoxyborohydride, sodiumcyanoborohydride, the borane-pyridine complex or catalytically excitedhydrogen is preferably used as the reducing agent.

[0052] Compounds having the formula I where X is CH₂—NH can also beobtained by alkylating a compound having the general formula VII,

[0053] in which R¹ and R² have the same meanings as above, withα-bromoglutarimide having the general formula VIII

[0054] Compounds having the general formula I, in which X stands for anS—CH₂ group, can be obtained by adding a mercaptan having the generalformula X

[0055] to 3-methylene glutarimide having the general formula IX

[0056] The reaction is preferably performed in solvents such asacetonitrile or toluene with addition of tertiary amines such astriethylamine or diisopropyl ethylamine at temperatures of 80 to 110° C.

[0057] Compounds having the formula I, in which R² stands for an aminogroup, can generally be obtained by reduction of compounds having theformula I where R²═NO₂. The reduction is performed, for example, bycatalytically excited hydrogen in acid-containing organic solvents suchas ethyl acetate, whereby palladium catalysts are preferably used.Alternatively, the reduction can be performed with metals such as tin oriron in acid solution.

[0058] The compounds according to the invention possess immunomodulatoryactivity which is demonstrated by an inhibition of the production ofIL-12 by LPS-activated monocytes. In comparison to compounds that havealready been proposed, they also demonstrate an improved hydrolyticstability. They are suitable for the treatment and/or prophylaxis ofinflammation and autoimmune diseases and also ofhaematological/oncological diseases.

[0059] Accordingly, the present invention also includes methods andpharmaceutical compositions for the treatment of these diseases. Themethod according to the invention comprises administering to a mammal,such as a human, in need thereof, an effective amount of a suitablepharmaceutical composition comprising a substituted glutarimide of theinvention.

[0060] The above groups of diseases include, amongst others,inflammations of the skin (e.g. atopic dermatitis, psoriasis, eczema),inflammations of the respiratory tracts (e.g. bronchitis, pneumonia,bronchial asthma, ARDS (adult respiratory distress syndrome),sarcoidosis, silicosis/fibrosis), inflammations of the gastrointestinaltract (e.g. gastroduodenal ulcers, Crohn's disease, ulcerative colitis),and diseases such as hepatitis, pancreatitis, appendicitis, peritonitis,nephritis, aphthosis, conjunctivitis, keratitis, uveitis, and rhinitis.

[0061] The autoimmune diseases include, for example, arthritic diseases(e.g. rheumatoid arthritis, HLA-B27-associated diseases), Behcet'sdisease, and multiple sclerosis, juvenile diabetes or lupuserythematosus.

[0062] Further indications are sepsis, bacterial meningitis, cachexia,transplant rejection reactions, graft-versus-host reactions as well asreperfusion syndrome and atherosclerosis along with angiopathies (suchas macula degeneration, diabetic retinopathies).

[0063] The symptoms that can be inhibited by a reduction in IL-12 alsoinclude haematological diseases such as multiple myeloma and leukaemias,along with other oncological diseases such as glioblastoma, prostatecancer and mammary cancer.

[0064] Medicaments according to the invention contain, in addition to atleast one compound having the general formula I, carriers, fillers,solvents, diluents, dyestuffs and/or binders. The choice of auxiliariesand the quantities to be used depend on whether the medicament is to beadministered by oral, rectal, ophthalmic (intravitreal, intracameral),nasal, topical (including buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous, intradermal,intratracheal and epidural) means.

[0065] Preparations in the form of tablets, chewable tablets,sugar-coated tablets, capsules, granules, drops, liquids or syrups aresuitable for oral administration, while solutions, suspensions, easilyreconstituted dry preparations and sprays are suitable foradministration by parenteral or topical means or by inhalation.Cutaneous administration forms are salves, gels, creams and pastes.Ophthalmic administration forms include drops, salves and gels.Compounds according to the invention contained in a reservoir indissolved form, a carrier film or a plaster, optionally with theaddition of skin-penetrating agents, are examples of suitablepercutaneous administration forms. The compounds according to theinvention can be released on a delayed basis from oral or percutaneousforms of preparation.

[0066] The amount of active agent to be administered to patients variesaccording to the weight of the patient, the type of administration, theindication and the severity of the disease. 1 to 150 mg/kg of at leastone compound according to the invention having the formula I areconventionally administered.

EXAMPLES

[0067] The following examples serve to describe the present invention ingreater detail, and should not be construed to limit the invention inany way.

[0068] Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was usedas stationary phase for the chromatographic separations. The mixingratios of the eluents are always given as percentages by volume.

[0069] The substances were characterised by their melting point and/orthe ¹H-NMR spectrum. The spectra were recorded at 300 MHz using a Gemini300 device from Varian. The chemical shifts are given in ppm (6-scale).Tetramethyl silane (TMS) was used as internal standard.

Example 1

[0070] 3-(2-chlorobenzylamino) piperidine-2,6-dione; hydrochloride

[0071] Step 1:

[0072] 3-bromopiperidine-2,6-dione

[0073] 4.5 ml bromine were added to 10.2 g glutarimide suspended in 20ml chloroform and the mixture was stirred in a closed vessel for 90minutes at a bath temperature of 110° C. After cooling, the vessel wasopened and stirring was continued until no more hydrogen bromideescaped. The reaction mixture was evaporated in vacuo, the residuedissolved in ethanol and evaporated again. 17.1 g (99% of theoretical)of the title compound remained in the form of practically whitecrystals, which melted at 76 to 83° C.

[0074] Step 2:

[0075] 3-(2-chlorobenzylamino) piperidine-2,6-dione; hydrochloride

[0076] A solution of 0.39 g of the product from step 1 and 0.71 g2-chlorobenzylamine in 8 ml N,N-dimethylformamide was stirred for 36hours at 20° C. After evaporation in vacuo the oily residue wasdissolved in 25 ml methanol and the solution stirred for two hours with1 g Amberlyst A-21. It was filtered, 2 g silica gel were added to thefiltrate and it was evaporated until dry. The adsorbed substance wasplaced in a chromatography column and the product was eluted with amixture of ethyl acetate/cyclohexane (1/2>1/1) containing 1%triethylamine. The residue remaining after evaporation of the productfractions was dissolved in 10 ml methanol and 25 ml each of diethylether saturated with hydrogen chloride and diethyl ether were added tothe solution. The precipitated hydrochloride was separated off andrecrystallised from methanol/diethyl ether. 0.24 g (41% of theoretical)of the title compound were obtained in the form of crystals, whichmelted at 217° C. with decomposition.

[0077]¹H-NMR (DMSO-d₆): 2.15-2.34 (1H, m); 2.40-2.56 (1H, m); 2.60-2.80(2H, m); 4.35 (1H, t, J=13.5 Hz); 4.45 (2H, d, J=13.8 Hz); 7.40-7.94(4H, m).

Example 2

[0078] Using the procedure described in Example 1, step 2 and thecorresponding benzylamines, the following compounds were obtained in thesame way:

[0079] 2.1: 3-(2-trifluoromethyl benzylamino) piperidine-2,6-dione;hydrochloride

[0080] Melting point: >250° C. (decomposition)

[0081] 2.2: 3-(2,4-dimethoxybenzylamino) piperidine-2,6-dione;hydrochloride

[0082] Melting point: 214° C. (decomposition)

[0083] 2.3: 3-(2,6-difluorobenzylamino) piperidine-2,6-dione;hydrochloride

[0084] Melting point: 208-215° C. (decomposition)

[0085] 2.4: 3-(2,5-difluorobenzylamino) piperidine-2,6-dione;hydrochloride

[0086] Melting point: 208° C. (decomposition)

[0087] 2.5: 3-(3,5-difluorobenzylamino) piperidine-2,6-dione;hydrochloride

[0088] Melting point: 230-236° C. (decomposition)

[0089] 2.6: 3-[(naphth-1-ylmethyl)amino] piperidine-2,6-dione;hydrochloride

[0090] Melting point: 188° C. (decomposition)

[0091] 2.7: 3-(2,3-difluorobenzylamino) piperidine-2,6-dione;hydrochloride

[0092] Melting point: 206-212° C. (decomposition)

[0093] 2.8: 3-(4-dimethylaminobenzylamino) piperidine-2,6-dione; base

[0094] 2.9: 3-(4-nitrobenzylamino) piperidine-2,6-dione; hydrochloride

[0095] 2.10: 3-(3-trifluoromethylbenzylamino) piperidine-2,6-dione;hydrochloride

[0096] 2.11: 3-(3-trifluoromethoxybenzylamino) piperidine-2,6-dione;hydrochloride

[0097] Melting point: 199-201° C.

[0098] 2.12: 3-[(naphth-2-ylmethyl)amino] piperidine-2,6-dione, base

[0099] Melting point: 120-125° C. (decomposition)

[0100] 2.13: 3-(2-chloro-4-fluorobenzylamino) piperidine-2,6-dione;hydrochloride

[0101] Melting point: 241-242° C.

[0102] 2.14: 3-(3-nitrobenzylamino) piperidine-2,6-dione; hydrochloride

[0103] Melting point: from 240° C. with decomposition

[0104] 2.15: 3-(2-chloro-6-methylbenzylamino) piperidine-2,6-dione;hydrochloride

[0105] Melting point: 238-240° C.

[0106] 2.16: 3-(2-methylbenzylamino) piperidine-2,6-dione; hydrochloride

[0107] Melting point: 235-240° C.

[0108] 2.17: 3-(3,5-dichlorobenzylamino) piperidine-2,6-dione;hydrochloride

[0109] Melting point: 234-238° C.

[0110] 2.18: 3-[3-fluoro-5-(trifluoromethyl) benzylamino]piperidine-2,6-dione; hydrochloride

[0111] Melting point: 241-243° C.

[0112] 2.19: 3-(3-fluorobenzylamino) piperidine-2,6-dione; hydrochloride

[0113] Melting point: 231-235° C.

[0114] 2.20: 3-(3-methylbenzylamino) piperidine-2,6-dione; hydrochloride

[0115] Melting point: 240-242° C.

[0116] 2.21: 3-(4-trifluoromethylbenzylamino) piperidine-2,6-dione;hydrochloride

[0117] Melting point: 252-255° C.

[0118] 2.22: 3-[4-fluoro-2-(trifluoromethyl) benzylamino]piperidine-2,6-dione; hydrochloride

[0119] Melting point: from 241° C. with decomposition

[0120] 2.23: 3-(4-fluorobenzylamino) piperidine-2,6-dione; hydrochloride

[0121] Melting point: 241-242° C.

[0122] 2.24: 3-(4-tert-butylbenzylamino) piperidine-2,6-dione;hydrochloride

[0123] Melting point: from 239° C. with decomposition

[0124] 2.25: 3-(3,5-dimethylbenzylamino) piperidine-2,6-dione;hydrochloride

[0125] Melting point: from 226° C. with decomposition

[0126] 2.26: 3-(3-chlorobenzylamino) piperidine-2,6-dione; hydrochloride

[0127] Melting point: 237-238° C.

[0128] 2.27: 3-(4-methoxybenzylamino) piperidine-2,6-dione;hydrochloride

[0129] Melting point: from 227° C. with decomposition

[0130] 2.28: 3-(2,4-dichlorobenzylamino) piperidine-2,6-dione;hydrochloride

[0131] Melting point: 240-242° C.

[0132] 2.29: 3-(2-fluorobenzylamino) piperidine-2,6-dione; hydrochloride

[0133] Melting point: 245-247° C.

[0134] 2.30: 3-(2-bromobenzylamino) piperidine-2,6-dione; hydrochloride

[0135] Melting point: 244-246° C.

[0136] 2.31: 3-[2-fluoro-5-(trifluoromethyl) benzylamino]piperidine-2,6-dione; hydrochloride

[0137] Melting point: from 251° C. with decomposition

[0138] 2.32: 3-(2,3-dichlorobenzylamino) piperidine-2,6-dione;hydrochloride

[0139] Melting point: 246-248° C.

[0140] 2.33: 3-(3,4-dichlorobenzylamino) piperidine-2,6-dione;hydrochloride

[0141] Melting point: 252-254° C.

[0142] 2.34: 3-[3,5-bis(trifluoromethyl) benzylamino]piperidine-2,6-dione; hydrochloride

[0143] Melting point: 263-265° C.

[0144] 2.35: 3-(3-bromobenzylamino) piperidine-2,6-dione; hydrochloride

[0145] Melting point: 229-232° C.

[0146] 2.36: 3-(4-trifluoromethoxybenzylamino) piperidine-2,6-dione;hydrochloride

[0147] Melting point: 253-255° C.

[0148] 2.37: 3-(4-chlorobenzylamino) piperidine-2,6-dione; hydrochloride

[0149] Melting point: 262-265° C.

[0150] 2.38: 3-(4-methylbenzylamino) piperidine-2,6-dione; hydrochloride

[0151] Melting point: 256° C. with decomposition

[0152] 2.39: 3-(2-ethoxybenzylamino) piperidine-2,6-dione; hydrochloride

[0153] Melting point: 208-212° C.

[0154] 2.40: 3-(2,5-dichlorobenzylamino) piperidine-2,6-dione;hydrochloride

[0155] Melting point: 242-246° C.

[0156] 2.41: 3-(3-methoxybenzylamino) piperidine-2,6-dione;hydrochloride

[0157] Melting point: 217-219° C.

[0158] All compounds listed under 2.1 to 2.41 are in the form of theracemate.

Example 3

[0159] 3-(3-aminobenzylamino) piperidine-2,6-dione; hydrochloride

[0160] 0.56 g of the product from example 2.14 in a mixture consistingof 17 ml ethyl acetate and 0.85 ml 6N hydrochloric acid werehydrogenated at 20° C. under a pressure of 4 bar over 0.17 g palladiumon activated carbon (10% Pd). After consumption of the theoreticalamount of hydrogen, the mixture was filtered off from the catalyst andthe filtrate evaporated in vacuo. After recrystallisation of the residuefrom methanol, 0.25 g (50% of theoretical) of the racemic title compoundwere obtained in the form of slightly colored crystals, which melted at236-239° C.

[0161]¹H-NMR (DMSO-d₆): 2.05-2.20 (m, 1H); 2.28-2.39 (m, 1H); 2.55-2.74(m, 2H); 3.97-4.12 (q, 2H); 4.18-4.28 (m, 1H); 6.58-6.70 (m, 3H);7.02-7.11 (m, 1H).

Example 4

[0162] Using the procedure described in Example 1, step 2 and thecorresponding arylalkylamines, the following compounds were obtained inthe same way:

[0163] 4.1: 3-phenethylaminopiperidine-2,6-dione; hydrochloride

[0164] Melting point: from 220° C. with decomposition

[0165] 4.2: 3-[2-(2-chlorophenyl) ethylaminopiperidine-2,6-dione;hydrochloride

[0166] Melting point: 230° C. (decomposition)

[0167] 4.3: 3-(4-phenylbutylamino) piperidine-2,6-dione; hydrochloride

[0168] Melting point: from 231° C. with decomposition

[0169] 4.4: 3-(N-benzyl-N-methylamino) piperidine-2,6-dione; base

[0170] Melting point: 95-115° C.

[0171] 4.5: 3-(methylnaphth-1-yl methylamino) piperidine-2,6-dione; base

[0172] Melting point: 157-162° C.

[0173] All compounds listed under 4.1 to 4.5 are in racemic form.

[0174] 4.6: (2S)-[(3S) or (3R)-(2,6-dioxopiperidin-3-ylamino)] methylphenylacetate; hydrochloride

[0175] Melting point: 200-207° C.

[0176] 4.7: (2R)-[(3S) or (3R)-(2,6-dioxopiperidin-3-ylamino)] methylphenylacetate; hydrochloride

[0177] Melting point: 171-177° C. (decomposition)

[0178] 4.8: (2S)-[(3R,S)-(2,6-dioxopiperidin-3-ylamino)]-3-methylphenylpropionate; hydrochloride

[0179]  (mixture of diastereomers)

[0180] Melting point: 146-150° C. (decomposition)

Example 5

[0181] 3-benzylaminopiperidine-2,6-dione

[0182] A) A solution of 0.50 g 3-aminopiperidine-2,6-dione (K.Fickentscher, Arch. Pharm. 1974, 307, 840-844), 1.5 ml triethylamine and0.4 ml benzyl bromide was stirred for 20 h at 20° C. It was thenevaporated, the residue taken up in 50 ml aqueous potassium carbonatesolution (10% K₂CO₃) and the solution extracted twice with 40 ml ethylacetate each. The organic phases were washed with 50 ml each ofdistilled water and saturated sodium chloride solution, dried oversodium sulfate and evaporated in vacuo. The residue was purified byflash chromatography on silica gel with a mixture of ethylacetate/cyclohexane (2/1) containing 1% triethylamine as eluent, whereby0.21 g (26% of theoretical) of the title compound was obtained asviscous oil.

[0183] The title compound could also be obtained in the form of thehydrobromide as pure S enantiomer in the following way:

[0184] B) Step 1:

[0185]  (2S)-(N-benzyl-N-benzyloxycarbonylamino)-4-carbamoyl butanoicacid

[0186]  0.6 ml benzyl chloroformate were added dropwise to 0.95 g(2S)-benzylamino-4-carbamoyl butanoic acid (E. Davidov et al., Isr. J.Chem. 1969, 7, 487-489) dissolved in 4 ml 2 M aqueous sodium hydroxideand 8 ml 1 M sodium hydrogen carbonate solution, over 2.5 h at 20° C.whilst being stirred. The mixture was then extracted twice with 20 mldiethyl ether each. The aqueous phase was acidified with conc.hydrochloric acid to pH 2-3 and extracted twice with 30 ml ethyl acetateeach. The extracts were washed with distilled water, dried over sodiumsulfate and evaporated in vacuo. After adding diethyl ether to the oilyresidue, 0.55 g (37% of theoretical) of the title compound were obtainedin the form of colorless crystals, which melted at 98-99° C.

[0187]  Step 2:

[0188]  (3S)—(N-butyl-N-benzyloxycarbonylamino) piperidine-2,6-dione

[0189]  A solution of 0.162 g N,N′-carbonyl diimidazole in 3 ml drytetrahydrofuran was dripped into a solution of 0.37 g of the productfrom step 1 in 2.5 ml dry tetrahydrofuran. It was refluxed for 3.5 hthen stirred for a further 3 h at 20° C. The oil remaining afterevaporation of the solvent in vacuo was dissolved in ethyl acetate andthe solution washed successively with 20 ml each of 1 M aqueous sodiumhydrogen carbonate solution, saturated sodium chloride solution anddistilled water. It was then dried over sodium sulfate and evaporated invacuo. 0.23 g (65% of theoretical) of the title compound remained in theform of crystals, which melted at 51-52° C.

[0190]  Step 3:

[0191]  (3S)-benzylaminopiperidine-2,6-dione; hydrobromide

[0192]  The solution of 0.15 g of the product from step 2 in 3 ml of asolution of hydrogen bromide in acetic acid (33% HBr) was stirred for 1h at 20° C. The reaction mixture was then poured onto 50 ml diethylether. The precipitate that was formed was separated off, washed withdiethyl ether and dried in vacuo. 0.08 g (63% of theoretical) of thetitle compound remained in the form of crystals, which melted at228-230° C. with decomposition.

[0193]¹H-NMR (DMSO-d₆): 2.01-2.43 (m, 2H); 2.60-2.80 (m, 2H); 4.20-4.45(m, 3H); 7.40-7.60 (m, 5H).

Example 6

[0194] 6.1 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,hydrobromide

[0195]  Step 1:

[0196]  2-[(1S)-(3-carbamoyl-1-carboxypropylamino)methyl] benzoic acid

[0197]  A suspension of 1.65 g 2-formylbenzoic acid in 5 ml ethanol and5 ml 2 M sodium hydroxide solution was added to a solution of 1.46 gL-glutamine in 5 ml of a 2 M aqueous sodium hydroxide solution. Afterstirring for 1 h at 20° C., the mixture was cooled to 0° C. and 0.25 gsodium borohydride were added in portions over 15 min with vigorousstirring. After 90 min a further 0.33 g 2-formyl benzoic acid and 0.05 gsodium borohydride were added. After stirring for 16 h at 20° C., thereaction mixture was acidified with conc. hydrochloric acid to pH 2 andcooled to 0° C. The precipitate formed was separated off, washed withacetone and dried in vacuo. 0.87 g (31% of theoretical) of the titlecompound remained in the form of crystals, which melted at 132-133° C.

[0198]  Step 2:

[0199] 2-{(1S)-[N-benzyloxycarbonyl-N-(3-carbamoyl-1-carboxypropyl)amino]methyl} benzoic acid

[0200]  Using the procedure described in Example 5 B, step 1, the titlecompound was obtained in the same way from the product from step 1 inthe form of crystals, which melted with decomposition at 103-104° C.

[0201]  Step 3:

[0202]  2-{(3S)-[N-benzyloxycarbonyl-N-(2,6-dioxopiperidin-3-yl)amino]methyl} benzoic acid

[0203]  Using the procedure described in Example 5 B, step 2, the titlecompound was obtained in the same way from the product from step 2 inthe form of crystals, which melted at 71-73° C.

[0204]  Step 4:

[0205]  2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,hydrobromide

[0206]  Using the procedure described in Example 5B, step 3, the titlecompound was obtained in the same way from the product from step 3 inthe form of colorless crystals, which melted at 158-161° C.

[0207]¹H-NMR (DMSO-d₆): 2.00-2.25 (m, 1H); 2.35-2.95 (m, 1H); 2.60-2.80(m, 2H); 4.35-4.50 (m, 1H); 4.50-4.70 (m, 2H); 7.50-7.75 (m, 3H);8.00-8.10 (m, 1H).

[0208] 6.2 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid;hydrobromide

[0209]  Replacing L- by D-glutamine in Example 6.1, step 1, and usingthe procedure described in Example 6.1, the title compound was obtainedin the same way in the form of crystals, which melted at 148-152° C.

Example 7

[0210]2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide;hydrobromide

[0211] Step 1:

[0212](3S)-[N-(2-diethylcarbamoylbenzyl)-N-benzyloxycarbonyl]aminopiperidine-2,6-dione

[0213] A solution of 1.00 g of the product from Example 6.1, step 3,0.27 g N-methyl morpholine and 0.46 g2-chloro-4,6-dimethoxy-1,3,5-triazine in 7 ml dry tetrahydrofuran wasstirred for 1 h at 20° C. After adding 0.19 g diethylamine, stirring wascontinued for a further 7 h. The solution was then diluted withchloroform to a volume of 50 ml and washed successively with 25 ml 0.05N hydrochloric acid, 25 ml 1 M aqueous sodium hydrogen carbonatesolution and saturated sodium chloride solution. The organic phase wasdried over sodium sulfate and evaporated in vacuo. After purifying theresidue by flash chromatography on silica gel with ethylacetate/cyclohexane (9/1) as eluent, 0.36 g (32% of theoretical) of thetitle compound were obtained in the form of crystals, which melted at65-66° C.

[0214] Step 2:

[0215] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide; hydrobromide

[0216] 0.30 g of the product from step 1 were reacted as described inExample 5B, step 3 with 3 ml of a solution of hydrogen bromide in aceticacid (33% HBr). After working up and purification by recrystallisationfrom methanol/diethyl ether, 0.175 g (66% of theoretical) of the titlecompound were obtained in the form of crystals, which melted at 119-120°C.

[0217]¹H-NMR (DMSO-d₆): 1.06 (t, J=7.5 Hz, 3H); 1.21 (t, J=6.9 Hz, 3H);2.04-2.24 (m, 1H); 2.28-2.46 (m, 2H); 2.58-2.80 (m, 2H); 3.19 (dd, 2H);3.51 (dd, 2H); 4.24 (s, 2H); 4.25-4.40 (m, 1H); 7.44 (d, 1H); 7.48-7.66(m, 2H); 7.72 (d, 1H).

Example 8

[0218] By replacing diethylamine in Example 7, step 1, by other amines,ammonia or hydrazine and using the additional procedure described inExample 7, the following were obtained in the same way:

[0219] 8.1: (3S)-[2-morpholine-4-carbonyl)benzylamino]piperidine-2,6-dione; hydrobromide

[0220] Melting point: 133-135° C.

[0221] 8.2: {2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoylamino}methyl acetate; hydrobromide

[0222] Melting point: 121-123° C.

[0223] 8.3: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide;hydrobromide

[0224] Melting point: 155-156° C. (decomposition)

[0225] 8.4: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethylbenzamide; hydrobromide

[0226] Melting point: 144-146° C.

[0227] 8.5: (3S)-[2-pyrrolidine-1-carbonyl)benzylamino]piperidin-2,6-dione; hydrobromide

[0228] Melting point: 136-138° C.

[0229] 8.6: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acidhydrazide; hydrobromide

[0230] Melting point: 241-242° C.

[0231] 8.7:2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenylbenzamide;hydrobromide

[0232] Melting point: 136-138° C.

[0233] 8.8: (2R)-{(3S)-2-[(2,6-dioxopiperidin-3-ylamino)methyl]benzoylamino} methyl phenylacetate; hydrobromide

[0234] Melting point: 149-151° C.

[0235] 8.9:(2S)-{(3S)-2-[(2,6-dioxopiperidin-3-ylamino)methyl]benzoylamino} methylphenylacetate; hydrobromide

[0236] Melting point: 181-182° C.

[0237] 8.10: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenylbenzamide; hydrobromide

[0238] Melting point: 168-171° C.

[0239] 8.11: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide; hydrobromide

[0240] Melting point: 128-132° C.

[0241] 8.12: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide;hydrobromide

[0242] Melting point: 232-233° C.

Example 9

[0243] 9.1: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methylbenzoate; hydrobromide

[0244] Step 1:

[0245]2-{(3S)-[N-benzyloxycarbonyl-N-(2,6-dioxopiperidin-3-yl)amino]-methyl}methyl benzoate

[0246] A mixture consisting of 0.60 g of the product from Example 6.1,step 3, and 0.25 g N,N′-carbonyl diimidazole in 5 ml dry tetrahydrofuranwas stirred for 1.5 h at 20° C. 64 μl methanol were then added andstirring was continued for a further 40 h at 20° C. After evaporatingoff the solvent in vacuo the residue was taken up in 80 ml chloroformand the solution washed with 1 M sodium hydrogen carbonate solution anddistilled water. It was dried over sodium sulfate and evaporated invacuo. After purification of the residue by column chromatography onsilica gel with chloroform/acetone (94/6) as eluent, 0.32 g (51% oftheoretical) of the title compound were obtained as a viscous oil.

[0247] Step 2:

[0248] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methyl benzoate;hydrobromide

[0249] By removing the benzyloxycarbonyl protective group in the productfrom step 1 using the procedure described in Example 5B, step 3, thetitle compound was obtained in the same way in the form of crystals,which melted at 187° C.

[0250]¹H-NMR (DMSO-d₆): 2.07-2.30 (m, 1H); 2.30-2.48 (m, 1H); 2.60-2.85(m, 2H); 3.90 (s, 3H); 4.40-4.70 (m, 3H); 7.58-7.78 (m, 3H); 8.05 (d,J=8 Hz, 1H).

[0251] 9.2: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzylbenzoate; hydrobromide

[0252] By replacing methanol with benzyl alcohol in Example 9.1 andusing the procedure described therein, the title compound was obtainedin the same way in the form of white crystals, which melted at 175-177°C.

Example 10

[0253] 3-phenylaminomethyl piperidine-2,6-dione

[0254] 30 ml absolute triethylamine and 2.75 ml freshly distilledaniline were added to a solution of 1.25 g 3-methylenepiperidine-2,6-dione (M. J. Wanner and G. -J. Koomen, Tetrahedron Lett.1992, 33, 1513-1516) in 100 ml acetonitrile and the mixture was stirredfor 16 h at 80° C.

[0255] After cooling, 10 g silica gel were added and the mixture wasevaporated in vacuo. The residue was purified by flash chromatography onsilica gel with tert-butyl methyl ether/cyclohexane (2/1) as eluent.1.87 g (86% of theoretical) of the title compound were obtained in theform of crystals, which melted at 137° C.

[0256]¹H-NMR (CDCl₃): 1.84-1.99 (m, 1H); 2.08-2.17 (m, 1H); 2.49-2.64(m, 1H); 2.73-2.83 (m, 2H); 3.41-3.50 (m, 1H); 3.60-3.70 (m, 1H);6.64-6.80 (m, 3H); 7.17-7.29 (m, 2H).

Example 11

[0257] By replacing aniline in Example 10 by other amines and using theprocedure therein described, whereby optionally the mixture oftoluene/diisopropyl ethylamine was also used instead of the solventsystem acetonitrile/triethylamine at a reaction temperature of 110° C.,the following compounds could be obtained in the same way:

[0258] 11.1: 3-[(4-bromophenylamino)methyl] piperidine-2,6-dione

[0259] Melting point: 149-150° C.

[0260] 11.2: 3-[(3-trifluoromethyl phenylamino)methyl]piperidine-2,6-dione

[0261] Melting point: 135-138° C.

[0262] 11.3: 3-(naphth-1-ylaminomethyl) piperidine-2,6-dione

[0263] Melting point: 145-148° C.

[0264] 11.4: 3-(biphenyl-4-ylaminomethyl) piperidine-2,6-dione

[0265] Melting point: 135-138° C.

[0266] 11.5: 3-[(3-methoxyphenylamino)methyl] piperidine-2,6-dione

[0267] Viscous

[0268] 11.6: 3-[(4-trityl phenylamino)methyl] piperidine-2,6-dione

[0269] Melting point: 221-225° C.

[0270] 11.7: 3-[(2,6-dioxopiperidin-3-ylmethyl)amino] ethyl benzoate

[0271] Viscous

[0272] 11.8: 3-(benzylaminomethyl) piperidine-2,6-dione

[0273] Viscous

[0274] 11.9: 3-[(3-acetyl phenylamino)methyl] piperidine-2,6-dione

[0275] Melting point: 129-132° C.

[0276] 11.10: 3-[(N-methyl-N-phenylamino)methyl] piperidine-2,6-dione

[0277] Melting point: 132-134° C.

[0278] 11.11: 3-{[(naphth-1-ylmethyl)amino] methyl} piperidine-2,6-dione

[0279] Viscous

[0280] 11.12: 3-[(2-methoxyphenylamino)methyl] piperidine-2,6-dione

[0281] Viscous

[0282] 11.13: 3-[(4-methoxyphenylamino)methyl] piperidine-2,6-dione

[0283] Melting point: 131-134° C.

[0284] 11.14: (2S)-[(2,6-dioxopiperidin-3-ylmethyl)amino]-3-methylphenylpropionate

[0285] Viscous

[0286] 11.15: 2-[(2,6-dioxopiperidin-3-ylmethyl)amino] benzamide

[0287] Melting point: 203-206° C.

[0288] 11.16: 3-[(4-acetylphenylamino)methyl] piperidine-2,6-dione

[0289] Melting point: 160° C.

[0290] 11.17: 3-[(3-benzoyl phenylamino)methyl] piperidine-2,6-dione

[0291] Melting point: 152-158° C.

[0292] 11.18: 4-[(2,6-dioxopiperidin-3-ylmethyl)amino] methyl benzoate

[0293] Melting point: 142-144° C.

Example 12

[0294] 3-[(2-hydroxymethyl phenylamino)methyl] piperidine-2,6-dione

[0295] Step 1:

[0296] 3-{[2-tert-butyl dimethyl silanyloxymethyl)phenylamino] methyl}piperidine-2,6-dione

[0297] By replacing aniline in Example 10 by 2-(tert-butyl dimethylsilanyloxymethyl) phenylamine and using the procedure therein described,the title compound was obtained in the form of white crystals, whichmelted at 85-87° C.

[0298] Step 2:

[0299] 3-[(2-hydroxymethyl phenylamino)methyl] piperidine-2,6-dione

[0300] 5 ml of a 1 M solution of tetrabutyl ammonium fluoride trihydratein tetrahydrofuran were added to a solution of 0.20 g of the productfrom step 1 in 5 ml tetrahydrofuran. It was stirred for 3 h at 20° C.,evaporated in vacuo and the residue was purified by flash chromatographyon silica gel with ethyl acetate as eluent. 0.12 g (85% of theoretical)of the title compound were obtained in the form of a yellowish oil.

Example 13

[0301] By replacing aniline in Example 10 by thiophenols or mercaptansand using the procedure therein described, the following were obtainedin the same way:

[0302] 13.1: 3-phenylsulfanylmethyl piperidine-2,6-dione

[0303] Melting point: 98° C.

[0304] 13.2: 3-phenethylsulfanylmethyl piperidine-2,6-dione

[0305] Melting point: 78° C.

[0306] 13.3: 2-(2,6-dioxopiperidin-3-ylmethyl)sulfanyl) methyl benzoate

[0307] Melting point: 142-144° C.

[0308] 13.4: 3-benzylsulfanylmethyl piperidine-2,6-dione

[0309] Melting point: 105-107° C.

[0310] 13.5: 3-(3-aminophenylsulfanylmethyl) piperidine-2,6-dione

[0311] Melting point: 133-135° C.

[0312] 13.6: 5-(2,6-dioxopiperidin-3-ylmethylsulfanyl)-6-nitromethylbenzoate

[0313] Melting point: 147-150° C.

Example 14

[0314] 2-amino-5-(2,6-dioxopiperidin-3-ylmethylsulfanyl) Methyl Benzoate

[0315] The title compound was obtained in the same way by catalytichydrogenation of the product from Example 13.6 over palladium onactivated carbon (10% Pd) under the conditions described in Example 3.

[0316] Melting point: 164-167° C.

Example 15

[0317] 3-phenylsulfanylmethyl-1-piperidin-1-ylmethylpiperidine-2,6-dione

[0318] 0.52 ml aqueous formaldehyde solution (35%) and 0.43 mlpiperidine were added to a solution of 1.20 g of the product fromExample 13.1 in 30 ml ethanol. After being refluxed for 1 hour, themixture was evaporated in vacuo. The residue was taken up in ethylacetate and n-hexane was added to the solution until precipitation. Thecrystals were separated off and dried in vacuo. 1.23 g (74% oftheoretical) of the title compound were obtained, which displayed amelting point of 63-66° C.

[0319]¹H-NMR (DMSO-d₆): 1.37-1.47 (m, 6H), 1.72-1.88 (m, 1H), 2.08-2.16(m, 1H), 2.21-2.33 (m, 4H), 2.49-2.57 (m, 1H), 2.70-2.82 (m, 1H),3.07-3.18 (m, 1H), 3.28-3.33 (m, 1H), 3.47-3.56 (m, 1H), 4.56-4.69 (m,2H), 7.17-7.25 (m, 1H), 7.28-7.39 (m, 4H).

Example 16

[0320] N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} acetamide;hydrobromide

[0321] Step 1:

[0322] 2[(2-acetyl aminobenzyl) benzyloxycarbonylamino]-4-carbamoylButanoic Acid

[0323] 1.20 g N-(2-formyl phenyl) acetamide, dissolved in 10 ml methanoland 3.7 ml 1 N sodium hydroxide solution, were added to a solution of0.98 g L-glutamine in 3.4 ml 2N sodium hydroxide solution, stirred for30 minutes at 20° C. and cooled to 0° C. 0.31 g sodium borohydride werethen added in portions with stirring over 30 minutes. Stirring wascontinued for 16 hours at 0 to 5° C. and 14.2 ml of a 1N aqueous sodiumhydrogen carbonate solution were then added. A solution of 1.4 ml benzyloxycarbonyl chloride in 1.1 ml tetrahydrofuran and 2.5 ml 4N sodiumhydroxide solution were then simultaneously added dropwise over onehour. Stirring was continued for 2 hours at 20° C. The neutral reactionsolution was extracted three times with diethyl ether and the aqueousphase then adjusted to pH 1 to 2 with 1N hydrochloric acid. It was thenextracted three times with 20 ml ethyl acetate. The combined organicphases were washed with 20 ml saturated sodium chloride solution, driedover sodium sulfate and evaporated in vacuo. 0.93 g of the unpurifiedtitle compound were obtained, which were then reacted further.

[0324] Step 2:

[0325] (2-acetylaminobenzyl)-(2,6-dioxopiperidin-3-yl) Benzyl Carbamate

[0326] A solution of 0.36 g carbonyl diimidazole in 3 ml absolutetetrahydrofuran was added to a solution of 0.90 g of the product fromstep 1 in 6 ml anhydrous tetrahydrofuran. The mixture was refluxed for 4hours. After evaporation of the solvent in vacuo, the residue was takenup in 50 ml distilled water and extracted three times with 50 ml ethylacetate. The extracts were first washed three times with 50 ml water,then with saturated sodium chloride solution, dried over sodium sulfateand evaporated in vacuo. 0.25 g (11% of theoretical, relative to theL-glutamine used in step 1) of the title compound were obtained by flashchromatography on silica gel with ethyl acetate/cyclohexane (2/1).

[0327] Step 3:

[0328] N-{2-[(2,6-dioxopiperidin-3-ylamino)methyl] phenyl} acetamide;hydrobromide

[0329] 1 ml of a solution of hydrogen bromide in glacial acetic acid(33% HBr) was added to a suspension of 0.20 g of the product from step 2in 1 ml glacial acetic acid. The mixture was stirred for 1 hour at 20°C. and then poured into 100 ml diethyl ether. After cooling to 0 to 5°C. the solid that had formed was separated off, washed with diethylether and dried in vacuo. After reprecipitation from methanol/diethylether, 0.09 g (50% of theoretical) of the title compound were obtained.

[0330] Melting point: 152-156° C.

[0331]¹H-NMR (DMSO-d₆): 2.05-2.22 (m, 1H); 2.13 (s, 3H); 2.35-2.74 (m,1H); 2.69-2.74 (m, 2H); 4.26 (s, 2H); 4.43 (d, 1H); 7.33-7.60 (m, 4H);9.88 (s, 1H); 11.41 (s, 1H).

Example 17

[0332] N-{2-[(2,6-dioxopiperidin-3-ylamino)methyl] phenyl} Formamide;Hydrobromide

[0333] By replacing the acetamide derivative used in Example 16, step 1,with N-(2-formyl phenyl) formamide and using the procedure described insteps 1 to 3, the title compound was obtained in the same way.

[0334] Melting point: 169-174° C.

Example 18

[0335] 3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitroMethylbenzoate

[0336] The title compound was produced using the procedure described inExample 10, by replacing the aniline with the corresponding mercaptan(formula X with R¹═COOCH₃ in the 3 position and R²═NO₂ in the 4position).

[0337] Melting point: 147-150° C.

Example 19

[0338] 2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) MethylBenzoate

[0339] The title compound was obtained in the same way by catalytichydrogenation of the product from Example 18 over palladium on activatedcarbon (10% Pd) under the conditions described in Example 3.

[0340] Melting point: 164-167° C.

[0341] Stimulation of human monocytes with lipopolysaccharide forsecretion of IL-12

[0342] Human monocytes were isolated from peripheral blood mononuclearcells (PBMC) obtained by means of a Ficoll density-gradientcentrifugation of heparinized whole blood. To this end, the PBMC wereincubated with a monoclonal antibody directed against themonocyte-specific surface molecule CD14 and to which superparamagneticmicrobeads (Miltenyi Biotech, Bergisch Gladbach) are coupled. In orderfor the marked monocytes to be positively selected from the mixture ofcells in the PBMC, the total cell suspension was transferred to a columnwith a ferromagnetic carrier matrix and the column placed in a magneticfield. This caused the cells loaded with microbeads to be bonded to thecarrier matrix, whilst unmarked cells passed through the column and werediscarded. After removing the matrix from the magnetic field, theantibody-loaded cells were eluted by rinsing the now demagnetised columnwith buffer. The purity of this CD 14-positive monocyte population thusobtained was around 95 to 98%. These monocytes were incubated in adensity of 10⁶ cells/ml culture medium (RPMI, supplemented with 10%fetal calf serum) with the test substances dissolved in DMSO for onehour at 37° C. and 5% CO₂.20 μg/ml LPS from E. coli were then added.After 24 hours, cell-free culture supernatants were taken and tested fortheir IL-12 content.

[0343] The concentration of IL-12 in the cell culture supernatants wasdetermined by means of sandwich ELISA using two anti-IL-12 monoclonalantibodies (Biosource Europe, Fleurus, Belgium). A reference standardcurve with human IL-12 was included. The detection limit of the IL-12ELISA was 10 pg/ml. TABLE 1 Influence of the test substances on IL-12production by LPS-activated monocytes. Inhibition of IL-12 productionExample no. Maximum (%) IC50 (μg/ml) 6.1 85 1.0 6.2 75 1.0 9.1 90 0.19.2 82 1.5 8.3 90 0.15 8.12 84 1.0 7 90 1.5 8.11 90 0.2 8.1 90 1.8 8.580 2.0 8.4 80 0.9 8.7 55 0.7 8.10 50 — 8.6 90 0.04 8.2 70 1.8 13.3 506.0 16 95 3.0 17 98 0.02 18 57 3.0 19 66 5.0

[0344] The results set out in Table 1 show that the substitutedglutarimides have an immunomodulatory action. They exert a potentinhibitory effect on the synthesis of IL-12 by LPS-activated monocytes.

[0345] The foregoing description and examples have been set forth merelyto illustrate invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations fallingwithin the appended claims and equivalents thereof.

We claim:
 1. A substituted glutarimide compound of formula I

wherein X is CH₂—NH or S—CH₂, R¹ is a carboxyl group; an ester grouphaving the formula COOR⁵ in which R⁵ is a C₁-C₆ straight-chain orbranched alkyl group or a benzyl group; or an amide group having theformula CONR⁶R⁷, in which R⁶ and R⁷ are the same or different andrepresent a hydrogen; a C₁-C₆ straight-chain or branched alkyl groupoptionally substituted with a COOR⁵ group or a phenyl group or both; ora phenyl group; or R⁶ and R⁷ taken together with the N atom represent ahydrazide group; a pyrrolidine; a piperidine or a morpholine ring; or anamino group substituted with a CH(═O) or COR⁵; and R² is a hydrogen, anamino or a nitro group, or a salt thereof with a physiologicallycompatible acid.
 2. An enantiomer, or a salt thereof with aphysiologically compatible acid, of a compound according to claim
 1. 3.A mixture of enantiomers, or salts thereof with a physiologicallycompatible acid, of at least a compound according to claim
 1. 4. Aracemate, or a salt thereof with a physiologically compatible acid, of acompound according to claim
 1. 5. A diastereomer, or mixture ofdiastereomers thereof, or a salt thereof with a physiologicallycompatible acid, of a compound according to claim
 1. 6. A compoundaccording to claim 1, selected from the group consisting of:2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,2-[(3S)-(2,6-dioxopiperidin-3-ylamino) methyl]-N,N-diethylbenzamide,(3S)-[2-morpholine-4-carbonyl)benzylamino] piperidine-2,6-dione,{2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoylamino} methylacetate, 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl benzamide,(3S)-[2-pyrrolidine-1-carbonyl)benzylamino] piperidine-2,6-dione,2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid hydrazide,2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethyl benzamide,2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methyl benzoate,2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzyl benzoate,2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate,N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} acetamide,N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} formamide,3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitro methylbenzoate, and2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate. 7.A pharmaceutical composition comprising as an active agent at least onecompound according to claim 1, and a pharmaceutically acceptableexcipient.
 8. A method for modulating immune action in a mammal in needthereof, comprising administering to the mammal an effectiveimmunomodulatory amount of a compound of claim
 1. 9. A method accordingto claim 8, wherein the mammal is a human.
 10. A method for thetreatment of angiopathies, or hematological or oncological diseases,comprising administering to a patient in need thereof an effectiveamount of a compound according to claim
 1. 11. A method for theproduction of a substituted glutarimide compound according to claim 1,the method comprising cyclizing a glutaric acid derivative of formulaII,

wherein X, R¹ and R² are as defined in formula I; and A is OH, and B isNH₂ or NHOH; or A is NH₂ or NHOH, and B is OH, in the presence of anactivating reagent.
 12. A method according to claim 11, wherein theactivating agent is carbonyl diimidazole.
 13. A method according toclaim 11, wherein X is CH₂—NH, and wherein cyclization is performed withthe —NH group of X protected by a protective group, which protectivegroup is removed after cyclization.
 14. A method according to claim 13,wherein the protective group is a benzyloxycarbonyl group.
 15. A methodfor the production of a substituted glutarimide compound according toclaim 1, the method comprising heating a glutaric acid derivative offormula II,

wherein X, R¹ and R² are as defined in formula I, and A and B are bothOH, in acetic anhydride to obtain an anhydride by cyclization, andheating the anhydride with a nitrogen source to obtain a compound offormula I.
 16. A method according to claim 15, wherein the nitrogensource is urea.
 17. A method for producing a substituted glutarimide offormula I according to claim 1, the method comprising oxidizing a lactamof formula III

in which R¹, R² and X are as defined for formula I, thereby convertingthe lactam to a corresponding imide.
 18. A method according to claim 17,wherein the lactam is oxidized with at least one oxidizer selected fromthe group consistin of m-chloroperbenzoic acid, ruthenium(IV) oxide andsodium periodate.
 19. A method for producing a substituted glutarimideof formula I according to claim 1 wherein X stands for a CH₂—NH group,the method comprising alkylating an α-aminoglutarimide compound offormula IV,

with a compound of formula V,

in which R¹ and R² are as defined for formula I, and Y is selected fromthe group consisting of chlorine, bromine, iodine, and atoluene-4-sulfonate group.
 20. A method for producing a substitutedglutarimide of formula I according to claim 1 wherein X stands for aCH₂—NH group, the method comprising reacting by reductive amination acompound of formula VI with a compound of formula IV,

in which R¹ and R² are as defined for formula I, to obtain thesubstituted glutarimide.
 21. A method according to claim 20, wherein thecompound of formula VI and the compound of formula IV are reduced by amember selected from the group consisting of sodium borohydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride, a borane-pyridinecomplex, and a catalytically excited hydrogen.
 22. A method forproducing a substituted glutarimide of formula I according to claim 1wherein X is a CH₂—NH group, the method comprising: alkylating acompound of formula VII,

in which R¹ and R² are as defined for formula I, with anα-bromoglutarimide of formula VIII


23. A method for producing a substituted glutarimide of formula Iaccording to claim 1 wherein X is an S—CH₂ group, the method comprisingadding in a solvent a mercaptan of formula X

in which R1 and R2 are as defined for formula I, to a 3-methyleneglutarimide of formula IX,


24. A method according to claim 23, wherein the solvent is acetonitrileor toluene.
 25. A method according to claim 24 wherein the solventfurther comprises a tertiary amine.
 26. A method according to claim 25,wherein the tertiary amine is triethylamine or diisopropyl ethylamine.27. A method according to claim 24, wherein the mercaptan is added tothe 3-methylene glutarimide at a temperature between about 80° C. andabout 110° C.
 28. A method for producing a substituted glutarimide offormula I according to claim 1 wherein R² is an amino group, the methodcomprising reducing a compound of formula I wherein R²═NO₂ bycatalytically excited hydrogen in an acid-containing organic solvent.29. A method according to claim 28, wherein the organic solvent is ethylacetate.
 30. A method according to claim 28, wherein the reduction isperformed using a palladium catalyst or with a metal in an acidsolution.
 31. A method according to claim 30, wherein the metal is tinor iron.